The long-term objectives of this research program are to examine effectiveness and toxicity of replicating Herpes simplex virus 1 (HSV-1) mutants for treatment of malignancies. Patients with primary and secondary liver tumors that are unresectable have a poor prognosis, and current treatment options are inadequate. Thus, there is strong rationale for development of new and effective therapies. Viral replication in tumor cells leads to their destruction, with liberation of progeny virion that infect and destroy adjacent cancer cells in a process referred to as viral oncolysis. We have conducted research demonstrating effectiveness of HSV-1 mutants for oncolysis of liver tumors in preclinical models. One specific mutant, rRp450, replicates preferentially in liver tumors rather than normal liver following intravascular delivery. This selective viral replication dramatically reduces liver tumor burden and enhances animal survival. On the basis of these and several other preclinical studies, the National Cancer Institute Rapid Access to Intervention Development (RAID) program has taken responsibility of translating this lead discovery into a phase I clinical trial. Specifically, RAID is responsible for cGMP rRp450 production, IND-directed preclinical toxicology, and release of cGMP rRp450 to the Principal Investigator via the Cancer Therapy Evaluation Program. The proposed clinical trial is a phase I study of 4 weekly administrations of rRp450 into the hepatic artery of study subjects with unresectable primary or secondary liver tumors. Study objectives are to [i] determine maximum tolerated dose and dose-limiting toxicity; [ii] perform rRp450 pharmacokinetics and biodistribution; [iii] assess immunologic responses to rRp450; and [iv] perform pathologic and radiographic assessments of rRp450 effect on liver tumors and normal liver. This phase I trial uses a standard algorithm for dose escalation. Data from this trial are a necessary first step to determine whether further clinical study of this novel and promising therapy is warranted. These data will also provide insight into rRp450 mechanism of action. [unreadable] [unreadable]